Hypothalamic Kisspeptin Neurons and the Control of Homeostasis

Endocrinology ◽  
2021 ◽  
Author(s):  
Oline K Rønnekleiv ◽  
Jian Qiu ◽  
Martin J Kelly
Keyword(s):  
Hormone Receptors ◽  
Gaba Release ◽  
Synaptic Connections ◽  
Dorsomedial Nucleus ◽  
Fed State ◽  
Excitatory Transmission ◽  
Gnrh Neurons ◽  
Gnrh Release ◽  
Estrous Cyclicity ◽  
Metabolic Hormone

Abstract Hypothalamic kisspeptin (Kiss1) neurons provide indispensable excitatory transmission to GnRH neurons for the coordinated release of gonadotropins, estrous cyclicity and ovulation. But maintaining reproductive functions is metabolically demanding so there must be a coordination with multiple homeostatic functions, and it is apparent that Kiss1 neurons play that role. There are two distinct populations of hypothalamic Kiss1 neurons, namely arcuate nucleus (Kiss1 ARH) neurons and anteroventral periventricular and periventricular nucleus (Kiss1 AVPV/PeN) neurons in rodents, both of which excite GnRH neurons via kisspeptin release but are differentially regulated by ovarian steroids. Estradiol (E2) increases the expression of kisspeptin in Kiss1 AVPV/PeN neurons but decreases its expression in Kiss1 ARH neurons. Also, Kiss1 ARH neurons co-express glutamate and Kiss1 AVPV/PeN neurons co-express GABA, both of which are upregulated by E2 in females. Also, Kiss1 ARH neurons express critical metabolic hormone receptors, and these neurons are excited by insulin and leptin during the fed state. Moreover, Kiss1 ARH neurons project to and excite the anorexigenic proopiomelanocortin (POMC) neurons but inhibit the orexigenic neuropeptide Y/Agouti-related peptide (NPY/AgRP) neurons, highlighting their role in regulating feeding behavior. Kiss1 ARH and Kiss1 AVPV/PeN neurons also project to the pre-autonomic paraventricular nucleus (satiety) neurons and the dorsomedial nucleus (energy expenditure) neurons to differentially regulate their function via glutamate and GABA release, respectively. Therefore, this review will address not only how Kiss1 neurons govern GnRH release, but how they control other homeostatic functions through their peptidergic, glutamatergic and GABAergic synaptic connections, providing further evidence that Kiss1 neurons are the key neurons coordinating energy states with reproduction.

scholarly journals Arcuate Kisspeptin Neurons Coordinate Reproductive Activities with Metabolism

2019 ◽  
Vol 37 (03) ◽  
pp. 131-140 ◽  
Author(s):  
Oline K. Rønnekleiv ◽  
Jian Qiu ◽  
Martin J. Kelly
Keyword(s):  
Energy Homeostasis ◽  
Hormone Receptors ◽  
Neuronal Excitability ◽  
Steroid Hormone Receptors ◽  
Synaptic Connections ◽  
Gnrh Neurons ◽  
Gnrh Release ◽  
Energy States ◽  
Reproductive Activities ◽  
Metabolic Hormone

AbstractHypothalamic control of fertility is the quintessential homeostatic function. However, fertility is metabolically demanding; so, there must be coordination between energy states and reproductive functions. Because gonadotropin-releasing hormone (GnRH) neurons are devoid of many of the critical metabolic hormone receptors for sensing nutrient levels, it has long been recognized that the sensing of energy stores had to be done by neurons presynaptic to GnRH neurons. Some of the obvious players have been the anorexigenic proopiomelanocortin (POMC) and orexigenic neuropeptide Y (NPY)/agouti-related peptide (AgRP) neurons, both of which are in close apposition to the median eminence, a circumventricular organ. Indeed, POMC and NPY/AgRP neurons are inversely regulated by glucose and metabolic hormones including insulin and leptin. However, their synaptic connections with GnRH neurons are sparse and/or GnRH neurons are lacking the postsynaptic receptors to mediate the appropriate physiological response. Kisspeptin neurons were discovered in the early part of this century and subsequently shown to project to and control GnRH neuronal excitability. In fact, more recently the arcuate kisspeptin neurons have been identified as the command neurons driving pulsatile release of GnRH. Subsequently, it was shown that arcuate kisspeptin neurons express not only steroid hormone receptors but also metabolic hormone receptors such that similar to POMC neurons, they are excited by insulin and leptin. Therefore, based on the premise that arcuate kisspeptin neurons are the key neurons coordinating energy states with reproduction, we will review not only how these vital neurons control pulsatile GnRH release but how they control energy homeostasis through their synaptic connections with POMC and NPY/AgRP neurons and ultimately how E2 can regulate their excitability.

scholarly journals Nonclassical Estrogen Modulation of Presynaptic GABA Terminals Modulates Calcium Dynamics in Gonadotropin-Releasing Hormone Neurons

Endocrinology ◽  
2008 ◽  
Vol 149 (11) ◽  
pp. 5335-5344 ◽  
Author(s):  
Nicola Romanò ◽  
Kiho Lee ◽  
István M. Ábrahám ◽  
Christine L. Jasoni ◽  
Allan E. Herbison
Keyword(s):  
Action Potential ◽  
Green Fluorescence Protein ◽  
Cell Voltage ◽  
Gaba Release ◽  
Calcium Dynamics ◽  
Gaba A ◽  
Transgenic Mouse Line ◽  
Gnrh Neurons ◽  
Regulatory Effects ◽  
Postsynaptic Calcium

There is increasing recognition that estrogen exerts multifaceted regulatory effects on GnRH neurons. The acute effects of estrogen on calcium dynamics in these cells were examined using a transgenic mouse line that allows real-time measurement of intracellular calcium concentration ([Ca2+]i) in GnRH neurons in the acute brain slice preparation. 17-β-Estradiol (E2) at 100 pm–100 nm was found to activate [Ca2+]i transients in approximately 40% of GnRH neurons with an approximate 15-min latency. This effect was not replicated by E2-BSA, which limits E2 action to the membrane, 17-α-estradiol, the inactive isomer at classical estrogen receptors (ERs), or G-1 the GPR30 agonist. E2 continued to activate [Ca2+]i transients when transcription was blocked. An ER α-selective agonist was equally potent in activating [Ca2+]i transients, and E2 remained effective in ERβ knockout × GnRH-Pericam mice. E2’s activation of [Ca2+]i transients continued in the presence of tetrodotoxin, which blocks action potential-dependent transmission, but was abolished completely by the further addition of a γ-aminobutyric acid (GABA)A receptor antagonist. Exogenous GABA was found to initiate [Ca2+]i transients in GnRH neurons. Whole cell, voltage-clamp recordings of GnRH-green fluorescence protein neurons revealed that E2 generated discrete bursts of miniature inhibitory postsynaptic currents with a latency of approximately 15 min. These observations provide evidence for a new mechanism of nonclassical estrogen action within the brain. Estrogen interacts with the classical ERα at the level of the GABAergic nerve terminal to regulate action potential-independent GABA release that, in turn, controls postsynaptic calcium dynamics.

scholarly journals Autocrine Regulation of Gonadotropin-Releasing Hormone Secretion in Cultured Hypothalamic Neurons

Endocrinology ◽  
1999 ◽  
Vol 140 (3) ◽  
pp. 1423-1431 ◽  
Author(s):  
Lazar Z. Krsmanovic ◽  
Antonio J. Martinez-Fuentes ◽  
Krishan K. Arora ◽  
Nadia Mores ◽  
Carlos E. Navarro ◽  
...  
Keyword(s):  
Hormone Secretion ◽  
Receptor Activation ◽  
Gnrh Receptor ◽  
Hypothalamic Neurons ◽  
Gnrh Receptors ◽  
Pulsatile Gnrh ◽  
Gnrh Neurons ◽  
Gnrh Release ◽  
Hypothalamic Cells

Abstract Episodic hormone secretion is a characteristic feature of the hypothalamo-pituitary-gonadal system, in which the profile of gonadotropin release from pituitary gonadotrophs reflects the pulsatile secretory activity of GnRH-producing neurons in the hypothalamus. Pulsatile release of GnRH is also evident in vitro during perifusion of immortalized GnRH neurons (GT1–7 cells) and cultured fetal hypothalamic cells, which continue to produce bioactive GnRH for up to 2 months. Such cultures, as well as hypothalamic tissue from adult rats, express GnRH receptors as evidenced by the presence of high-affinity GnRH binding sites and GnRH receptor transcripts. Furthermore, individual GnRH neurons coexpress GnRH and GnRH receptors as revealed by double immunostaining of hypothalamic cultures. In static cultures of hypothalamic neurons and GT1–7 cells, treatment with the GnRH receptor antagonist, [d-pGlu1, d-Phe2, d-Trp3,6]GnRH caused a prominent increase in GnRH release. In perifused hypothalamic cells and GT1–7 cells, treatment with the GnRH receptor agonist, des-Gly10-[d-Ala6]GnRH N-ethylamide, reduced the frequency and increased the amplitude of pulsatile GnRH release, as previously observed in GT1–7 cells. In contrast, exposure to the GnRH antagonist analogs abolished pulsatile secretion and caused a sustained and progressive increase in GnRH release. These findings have demonstrated that GnRH receptors are expressed in hypothalamic GnRH neurons, and that receptor activation is required for pulsatile GnRH release in vitro. The effects of GnRH agonist and antagonist analogs on neuropeptide release are consistent with the operation of an ultrashort-loop autocrine feedback mechanism that exerts both positive and negative actions that are necessary for the integrated control of GnRH secretion from the hypothalamus.

scholarly journals Kisspeptin Increases γ-Aminobutyric Acidergic and Glutamatergic Transmission Directly to Gonadotropin-Releasing Hormone Neurons in an Estradiol-Dependent Manner

Endocrinology ◽  
2010 ◽  
Vol 151 (1) ◽  
pp. 291-300 ◽  
Author(s):  
Justyna Pielecka-Fortuna ◽  
Suzanne M. Moenter
Keyword(s):  
Negative Feedback ◽  
Positive Feedback ◽  
Brain Slices ◽  
Cell Voltage ◽  
Dependent Manner ◽  
Glutamatergic Transmission ◽  
Neuron Response ◽  
Gnrh Neurons ◽  
Gnrh Release ◽  
In Cells

Abstract GnRH neurons are the final central pathway controlling fertility. Kisspeptin potently activates GnRH release via G protein-coupled receptor 54 (GPR54). GnRH neurons express GPR54, and kisspeptin can act directly; however, GPR54 is broadly expressed, suggesting indirect actions are possible. Transsynaptic mechanisms are involved in estradiol-induced potentiation of GnRH neuron response to kisspeptin. To investigate these mechanisms, separate whole-cell voltage-clamp recordings were performed of γ-aminobutyric acid (GABA)-ergic and glutamatergic transmission to GnRH neurons in brain slices before and during kisspeptin treatment. To determine whether estradiol alters the effect of kisspeptin on synaptic transmission, mice were ovariectomized and either left with no further treatment (OVX) or treated with estradiol implants (OVX+E). Cells were first studied in the morning when estradiol exerts negative feedback. Kisspeptin increased frequency and amplitude of GABAergic postsynaptic currents (PSCs) in GnRH neurons from OVX+E mice. Blocking action potentials eliminated the effect on frequency, indicating presynaptic actions. Amplitude changes were due to postsynaptic actions. Kisspeptin also increased frequency of glutamatergic excitatory PSCs in cells from OVX+E animals. Kisspeptin did not affect either GABAergic or glutamatergic transmission to GnRH neurons in cells from OVX mice, indicating effects on transmission are estradiol dependent. In contrast to stimulatory effects on GABAergic PSC frequency during negative feedback, kisspeptin had no effect during positive feedback. These data suggest estradiol enables kisspeptin-mediated increases in GABA and glutamate transmission to GnRH neurons. Furthermore, the occlusion of the response during positive feedback implies one consequence of estradiol positive feedback is an increase in transmission to GnRH neurons mediated by endogenous kisspeptin.

scholarly journals Overexpression of Glutamic Acid Decarboxylase-67 (GAD-67) in Gonadotropin-Releasing Hormone Neurons Disrupts Migratory Fate and Female Reproductive Function in Mice

Endocrinology ◽  
2003 ◽  
Vol 144 (6) ◽  
pp. 2566-2579 ◽  
Author(s):  
Sabine Heger ◽  
Marianne Seney ◽  
Elizabeth Bless ◽  
Gerald A. Schwarting ◽  
Marie Bilger ◽  
...  
Keyword(s):  
Glutamic Acid Decarboxylase ◽  
Normal Values ◽  
Reproductive Function ◽  
Transgenic Animals ◽  
Mutant Mice ◽  
Acid Decarboxylase ◽  
Gaba Production ◽  
Gnrh Neurons ◽  
Gnrh Release ◽  
The Brain

Abstract γ-Aminobutyric acid (GABA) inhibits the embryonic migration of GnRH neurons and regulates hypothalamic GnRH release. A subset of GnRH neurons expresses GABA along their migratory route in the nasal compartment before entering the brain, suggesting that GABA produced by GnRH neurons may help regulate the migratory process. To examine this hypothesis and the possibility that persistence of GABA production by GnRH neurons may affect subsequent reproductive function, we generated transgenic mice in which the expression of glutamic acid decarboxylase-67 (GAD-67), a key enzyme in GABA synthesis, is targeted to GnRH neurons under the control of the GnRH gene promoter. On embryonic d 15, when GnRH neurons are still migrating, the transgenic animals had more GnRH neurons in aberrant locations in the cerebral cortex and fewer neurons reaching the hypothalamic-preoptic region, whereas migration into the brain was not affected. Hypothalamic GnRH content in mutant mice was low during the first week of postnatal life, increasing to normal values during infantile development (second week after birth) in the presence of increased pulsatile GnRH release. Consistent with these changes, serum LH and FSH levels were also elevated. Gonadotropin release returned to normal values by the time steroid negative feedback became established (fourth week of life). Ovariectomy at this time demonstrated an enhanced gonadotropin response in transgenic animals. Although the onset of puberty, as assessed by the age at vaginal opening and first ovulation, was not affected in the mutant mice, estrous cyclicity and adult reproductive capacity were disrupted. Mutant mice had reduced litter sizes, increased time intervals between deliveries of litters, and a shorter reproductive life span. Thus, GABA produced within GnRH neurons does not delay GnRH neuronal migration, but instead serves as a developmental cue that increases the positional diversity of these neurons within the basal forebrain. In addition, the results suggest that the timely termination of GABA production within the GnRH neuronal network is a prerequisite for normal reproductive function. The possibility arises that similar abnormalities in GABA homeostasis may contribute to syndromes of hypothalamic amenorrhea/oligomenorrhea in humans.

scholarly journals Kisspeptin cell-specific PI3K signaling regulates hypothalamic kisspeptin expression and participates in the regulation of female fertility

2014 ◽  
Vol 307 (11) ◽  
pp. E969-E982 ◽  
Author(s):  
Matthew Beymer ◽  
Ariel L. Negrón ◽  
Guiqin Yu ◽  
Samuel Wu ◽  
Christian Mayer ◽  
...  
Keyword(s):  
Intracellular Signaling ◽  
Pubertal Development ◽  
Cell Number ◽  
Pi3k Signaling ◽  
Catalytic Subunits ◽  
Gnrh Release ◽  
Estrous Cyclicity ◽  
Males And Females ◽  
Specific Deletion

Hypothalamic kisspeptin neurons integrate and translate cues from the internal and external environments that regulate gonadotropin-releasing hormone (GnRH) secretion and maintain fertility in mammals. However, the intracellular signaling pathways utilized to translate such information into changes in kisspeptin expression, release, and ultimately activation of the kisspeptin-receptive GnRH network have not yet been identified. PI3K is an important signaling node common to many peripheral factors known to regulate kisspeptin expression and GnRH release. We investigated whether PI3K signaling regulates hypothalamic kisspeptin expression, pubertal development, and adult fertility in mice. We generated mice with a kisspeptin cell-specific deletion of the PI3K catalytic subunits p110α and p110β (kiss-p110α/β-KO). Using in situ hybridization, we examined Kiss1 mRNA expression in gonad-intact, gonadectomized (Gdx), and Gdx + steroid-replaced mice. Kiss1 cell number in the anteroventral periventricular hypothalamus (AVPV) was significantly reduced in intact females but not in males. In contrast, compared with WT and regardless of steroid hormone status, Kiss1 cell number was lower in the arcuate (ARC) of kiss-p110α/β-KO males, but it was unaffected in females. Both intact Kiss-p110α/β-KO males and females had reduced ARC kisspeptin-immunoreactive (IR) fibers compared with WT animals. Adult kiss-p110α/β-KO males had significantly lower circulating luteinizing hormone (LH) levels, whereas pubertal development and fertility were unaffected in males. Kiss-p110α/β-KO females exhibited a reduction in fertility despite normal pubertal development, LH levels, and estrous cyclicity. Our data show that PI3K signaling is important for the regulation of hypothalamic kisspeptin expression and contributes to normal fertility in females.

Can obestatin modulate the GnRH neurons activity?

2016 ◽  
Vol 62 (5) ◽  
pp. 49-50 ◽  
Author(s):  
Michal Szlis ◽  
Jolanta Polkowska ◽  
Anna Wójcik-Gładysz
Keyword(s):  
Gene Expression ◽  
Central Nervous System ◽  
Nervous System ◽  
Pulse Generator ◽  
Receptor Gene ◽  
Secretory Activity ◽  
Gnrh Neurons ◽  
Gnrh Release ◽  
The Central Nervous System ◽  
Anorexigenic Peptide

Obestatin, an anorexigenic peptide acting at the central nervous system and on the periperial level, can co-create neuroendocrine network, which modulate the gonadotrophic axis activity. The aim of this study was to investigate the role of intracerebroventricular obestatin infusion on the activity of the gonadoliberine (GnRH) neurons activity.The experiment was performed on peripubertal Polish Merino sheep (n=24). Animals were divided into 2 groups: control (Ringer-Lock solution infusions; n=12) and experimental (obestatin infusion, 25μl/120μl/h; n=12). Infusions were performed over three consecutive days; blood samples were collected on day 0 and day 3. After the experiment, the animals were slaughtered, and the chosen brain tissue was preserved for IHC and Real Time RT-qPCR analysis.It was also shown that exogenous obestatin changes the selected gene expression of GnRH pulse generator, decreases the secretory activity of GnRH neurons, resulting from the inhibition of GnRH release from median eminence terminal nerves, and also decreases the GnRH receptor gene expression in pituitary. On the basis of the obtained results it can be concluded that obestatin may be involved in the modulation of reproduction processes in animals at the level of the central nervous system. However, the mechanism of its action requires further research, especially identifying the obestatin receptor itself.

scholarly journals Genetic Deletion of Esr1 in the Mouse Preoptic Area Disrupts the LH Surge and Estrous Cyclicity

Endocrinology ◽  
2019 ◽  
Vol 160 (8) ◽  
pp. 1821-1829 ◽  
Author(s):  
Robert Porteous ◽  
Allan E Herbison
Keyword(s):  
Estrogen Receptor ◽  
Third Ventricle ◽  
Estrogen Receptor Α ◽  
Adeno Associated Virus ◽  
Estrous Cycles ◽  
Lh Surge ◽  
Periventricular Nucleus ◽  
Gnrh Neurons ◽  
Estrous Cyclicity ◽  
Periventricular Area

Abstract Estrogen receptor α (ESR1) is critical for the generation of the preovulatory LH surge. Experiments in rodents have indicated a role for neurons located in the anteroventral periventricular area and preoptic periventricular nucleus [termed the rostral periventricular area of the third ventricle (RP3V)] in surge generation. In the current study, we aimed to examine whether ESR1 expressed by RP3V neurons was necessary for the LH surge. The estrous cycles of mice with estrogen receptor α (Esr1) exon 3 flanked by LoxP sites (Esr1 flox) and controls were monitored before and after bilateral stereotactic injection of adeno-associated virus encoding Cre recombinase into the RP3V. This resulted in 84% and 72% decreases in ESR1-immunoreactive cell numbers in the anteroventral periventricular area and preoptic periventricular nucleus, respectively, with no changes in the arcuate nucleus. Beginning three weeks after the adeno-associated virus injection, Esr1 flox mice began to show a loss of estrous cyclicity going, primarily, into constant estrus. Wild-type mice and Esr1 flox mice with injections outside the RP3V or unilateral ablations of ESR1 continued to exhibit normal estrous cycles. Mice were then gonadectomized and given an estradiol replacement regimen to generate the LH surge. This resulted in an absence of cFOS expression in GnRH neurons (1 ± 1% vs 28 ± 4% of GnRH neurons; P < 0.01) and markedly reduced LH surge levels (2.5 ± 0.6 vs 9.1 ± 1.0 ng/mL; P < 0.01) in Esr1 flox mice compared with controls. These results demonstrate that neurons expressing ESR1 within the RP3V are critical for the generation of the LH surge and estrous cyclicity in the mouse.

scholarly journals Interactions between neurotensin and GnRH neurons in the positive feedback control of GnRH/LH secretion in the mouse

2010 ◽  
Vol 298 (1) ◽  
pp. E80-E88 ◽  
Author(s):  
Heather M. Dungan Lemko ◽  
Roxana Naderi ◽  
Valeriya Adjan ◽  
Lothar H. Jennes ◽  
Victor M. Navarro ◽  
...  
Keyword(s):  
Basal Forebrain ◽  
Neural Circuits ◽  
Direct Role ◽  
Lh Surge ◽  
Periventricular Nucleus ◽  
Gnrh Neurons ◽  
Gnrh Release ◽  
Double Label ◽  
Lh Secretion

In female mammals, increased ovarian estradiol (E2) secretion triggers GnRH release from neurons in the basal forebrain, which drives LH secretion from the pituitary and subsequently induces ovulation. However, the neural circuits that activate this preovulatory GnRH/LH surge remain unidentified. Neurotensin is expressed in neurons of the anteroventral periventricular nucleus (AVPV), a region thought to be critical for generating the preovulatory GnRH/LH surge. E2 induces neurotensin ( Nts) gene expression in this region, and blockade of neurotensin signaling reduces the LH surge in the rat. We postulated that neurotensin signaling plays a similar role in generating the E2-induced GnRH/LH surge in mice. We used in situ hybridization (ISH) to determine whether E2 induces Nts expression in the mouse and found evidence to support this proposition. Next, we determined that the neurotensin receptor (Ntsr2) is present in many GnRH-expressing neurons. Since the kisspeptin gene ( Kiss1) is expressed in the AVPV and is responsive to E2, we predicted that some neurons in this region express both Kiss1 and Nts; however, by double-label ISH, we observed no coexpression of the two mRNAs. We also postulated that Nts mRNA expression would increase in parallel with the E2-induced LH surge and that the central (icv) administration of neurotensin would stimulate LH secretion and activation of GnRH neurons but found no evidence to support either of these hypotheses. Together, these findings suggest that, although neurotensin neurons in the AVPV are targets for regulation by E2, neurotensin does not appear to play a direct role in generating the GnRH/LH surge in the mouse.

scholarly journals STX, a Novel Nonsteroidal Estrogenic Compound, Induces Rapid Action in Primate GnRH Neuronal Calcium Dynamics and Peptide Release

Endocrinology ◽  
2011 ◽  
Vol 152 (8) ◽  
pp. 3182-3191 ◽  
Author(s):  
B. P. Kenealy ◽  
K. L. Keen ◽  
O. K. Rønnekleiv ◽  
E. Terasawa
Keyword(s):  
Small Interfering Rna ◽  
Membrane Receptors ◽  
Rna Transfection ◽  
Rapid Action ◽  
Peptide Release ◽  
Gnrh Neurons ◽  
Gnrh Release ◽  
Estrogenic Action ◽  
Induced Changes ◽  
Interfering Rna

Previously, we reported that 1 nm 17ß-estradiol (E2) induces a rapid action, which is, in part, mediated through the G protein-coupled receptor GPR30 in primate GnRH neurons. Because it has been reported that the diphenylacrylamide compound, STX, causes estrogenic action in the mouse and guinea pig hypothalamus, the present study examined effects of STX in primate GnRH neurons and whether there is an action independent of GPR30. Results are summarized as follows. STX (10 nm) exposure increased 1) the oscillation frequency of intracellular calcium concentration ([Ca2+]i), 2) the percentage of cells stimulated, and 3) the synchronization frequency of [Ca2+]i oscillations. STX (10–100 nm) also stimulated GnRH release. The effects of STX on both [Ca2+]i oscillations and GnRH release were similar to those caused by E2 (1 nm), although with less magnitude. STX (10 nm)-induced changes in [Ca2+]i oscillations were not altered by GPR30 small interfering RNA transfection, indicating that STX-sensitive receptors differ from GPR30. Finally, a higher dose of E2 (10 nm) induced a larger change in [Ca2+]i oscillations than that with a smaller dose of E2 (1 nm), and the effects of 10 nm E2 were reduced but not completely blocked by GPR30 small interfering RNA transfection, indicating that the effects of 10 nm E2 in primate GnRH neurons are mediated by multiple membrane receptors, including GPR30 and STX-sensitive receptors. Collectively, the rapid action of E2 mediated through GPR30 differs from that mediated through STX-sensitive receptors. The molecular structure of the STX-sensitive receptor remains to be identified.

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